Decentralised Procedure Public Assessment Report Sultiam

Decentralised Procedure

Public Assessment Report

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten

Sultiame

DE/H/4348/001-003/DC

Applicant: neuraxpharm Arzneimittel GmbH, Germany

Reference Member State DE TABLE OF CONTENTS

I. INTRODUCTION ...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 Problem statement ...... 4 II.2 About the product ...... 4 II.3 General comments on the submitted dossier ...... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 5 III.1 Quality aspects ...... 5 III.2 Non-clinical aspects ...... 6 III.3 Clinical aspects ...... 6 IV. BENEFIT RISK ASSESSMENT ...... 13

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 2/13 ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten product(s) in the RMS Name of the drug substance (INN Sultiame name): Pharmaco-therapeutic group N03AX03 (ATC Code): Pharmaceutical form(s) and Film-coated tablet; 50 / 100 / 200 mg strength(s): Reference Number(s) for the DE/H/4348/001-003/DC Decentralised Procedure Reference Member State: DE Member States concerned: LU withdrawn Applicant (name and address) neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Str. 23 40764 Langenfeld Germany neuraxpharm Arzneimittel GmbH Names and addresses of all proposed Elisabeth-Selbert-Str. 23 manufacturer(s) responsible for 40764 Langenfeld batch release in the EEA Germany

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 3/13 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten”, with the following indication:

The medicinal product is used for the alternative treatment for Rolandic epilepsy when the treatment with other anti-epileptics has not produced the desired effect.

Note: The treatment with Sultiame should only be performed by neuropaediatricians with experience in the treatment of epilepsy. The efficacy and safety of Sultiame for the above therapeutic indication have not been verified in controlled studies. Before starting a treatment with Sultiame careful differential diagnosis is required to distinguish the particular case from other forms of epilepsy in childhood. Rolandic epilepsy has a high spontaneous remission rate and in most cases a good outcome and a good prognosis - even without medication. is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement N/A

II.2 About the product Sultiame is a cyclic sulphonamide derivative. The structure of sultiame is distinct from that of other anticonvulsants. It has a carbonic anhydrase (CA) inhibitory effect which is used therapeutically as an antiepileptic drug. The exact mechanism of action of sultiame is not known. CAIs can reduce seizures through perturbation of the CO2 equilibrium and/or the inhibition of ion channels. Thus, sultiame may also act via sodium channels. Innovator products of sultiame for oral use have been approved and are marketed in several European and non-European countries.

The generally accepted indication of oral sultiame products is:

Alternative therapy of Rolandic epilepsy when treatment with other antiepileptics was unsuccessful.

Note: Treatment with sultiame should only be performed by a neuropaediatrician experienced in epilepsy therapy. Efficacy and safety of sultiame in the aforementioned indication has not been examined in controlled clinical studies. Before the start of therapy with sultiame, a careful differential diagnostic approach concerning other types of epilepsy in childhood is indicated. Rolandic epilepsy shows a high rate of spontaneous remission and has even without medicamentous therapy mostly favourable progress and a good prognosis.

II.3 General comments on the submitted dossier This decentralised application concerns a generic version of sultiame and has been submitted according to Art. 10(1) of Dir. 2001/83/EC under the trade names “Sultiam-neuraxpharm 50 / 200 mg Filmtabletten” and according to Art. 10(3) of Dir. 2001/83/EC under the trade name “Sultiam-neuraxpharm 100 mg Filmtabletten”. The originator product is “Ospolot 50 / 200 mg film- coated tablets” by Desitin Arzneimittel GmbH, Germany, registered since 3rd July1998. Hence, data protection has expired and generic products can be licensed. With Germany as the Reference Member State in this Decentralized Procedure, neuraxpharm Arzneimittel GmbH, Germany, has originally applied for the Marketing Authorisations for “Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten” in LU. However, the Company decided to withdraw marketing authorisation application for this procedure in LU due to economical reasons on August 8th, 2016.

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 4/13 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

The submitted bioequivalence study (No. 355B14) has been stated to have been performed in compliance with GCP. According to Eudra CT, no critical findings were reported for the inspections of the bioanalytical study site. With respect to the clinical study site an inspection performed by BfArM in 2006 revealed one or more critical findings. However no critical finding was identified during the inspection performed in 2013 by the AEMPS. The very recent inspection of this study site by BfArM (from 07 to 10 December 2015) revealed no critical and one or more major findings.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten are of sufficient quality in view of the present European regulatory requirements.

The route of synthesis has been adequately described. The drug substance manufacturer uses a multi- step synthesis followed by purification steps. The structure of Sultiame has been confirmed by spectroscopic analyses. The proposed drug substance specification is acceptable. The analytical test methods have been sufficiently described. Satisfactory batch analysis data of three commercial scale batches of Sultiame drug substance have been presented. Stability studies have been performed with the drug substance. The data presented support the claimed re-test period of 24 months.

Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The generic drug product and the innovator product exhibit the same qualitative and quantitative composition in terms of the active substance and the same pharmaceutical form. Bioequivalence of the two formulations has been demonstrated by an in vivo bioequivalence study of the 200 mg strength. The divisibility has been adequately demonstrated. As the Hardness of the tablets does not change over time no further testing is required. The manufacturing process has been adequately described.

The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on four batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 30 months without any labelled storage conditions for the drug product is considered justified by stability by extrapolation of 18 month long term data as no trends were detectable under any storage condition.

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 5/13 III.2 Non-clinical aspects The pharmacological and toxicological characteristics of sultiame are well established and have been satisfactorily summarised based on publicly available information in Module 2.4. This document also confirms that the excipients used in the drug product are well established. By reference to pertinent sections of Module 3, Module 2.4 clarifies that the inherent impurity profile of both drug substance and drug product complies with prevailing ICH and European requirements (CPMP/ICH2737/99; CPMP/ICH/2738/99; EMA/CHMP/ICH/82260/2006; EMEA/CHMP/QWP/251344/2006 and EMA/CHMP/SWP/431994/2007 Rev. 3). Thus, further toxicological qualification measures are not required. The instructions on use of sultiame during pregnancy and breast-feeding in section 4.6 of the SmPC and in the respective section in the PL as well as preclinical safety and fertility data in the SmPC have been revised to meet the current recommendations of the SmPC guidance and the QRD template.

Environmental Risk Assessment (ERA) Since “Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten” is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.3 Clinical aspects Pharmacokinetics To support the application, the applicant has submitted one bioequivalence study under fasting conditions (No. 355B14) with the 200 mg tablet strength and claims waiver of both lower tablet strengths (50 mg and 100 mg, respectively) referring to 'Guideline on the investigation of bioequivalence' (CPMP/EWP/QWP/1401/98 Rev.1).

Based on the submitted data bioequivalence of the intended Sultiam-neuraxpharm 200 mg Filmtabletten with the reference product Ospolot 200 mg has been shown,

Study 355B14 resulted in a statistically significantly higher Cmax (1-sided confidence interval in the range of 103.28-120.06, point estimate 111.36) as well as clearly faster increase in plasma concentrations (median tmax 0.67 (T) vs. 2.0 (R) hrs) after administration of the intended Sultiame- neuraxpharm 200 mg tablets compared to the reference product. However the primary pharmacokinetic endpoints have been met and the 90%Ci met conventional acceptance criteria.

The results of study 355B14 with 200 mg tablets can be extrapolated to the other strengths, 100 mg and 50 mg, respectively, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6

Pharmacodynamics/Clinical efficacy/Clinical safety No new studies on pharmacodynamics, clinical efficacy or safety have been submitted.

Legal Status Medicinal product is subject to medical prescription.

User Testing Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009;Update of Directive 2001/83/EC as amended by Directive 2004/27/EC/Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). In the preliminary round as well as in both main test rounds, 100% of participants were able to locate the correct information, and 100% of participants were able to answer all questions correctly. The general impression of the PL (content, language and layout) was mainly positive. In conclusion the user test is considered acceptable.

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 6/13 Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to “Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten”.

Summary of safety concerns The applicant provided the following summary of safety concerns in the RMP (module SVIII)

• Blood cytopenia including leucopenia, thrombocytopenia • Suicidal thoughts and behaviour Important identified risks • Abnormal behaviour including aggressiveness, mood swings • Hepatotoxic reactions • SJS/Lyell-syndrom • Nephrolithiasis • Metabolic acidosis Important potential risks • Renal impairment • Psychotic disorders

Missing information • Use during pregnancy and lactation

The proposed safety concerns are acceptable.

Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 7/13 Risk minimisation plan Summary of safety concerns and planned risk minimisation activities as proposed in the RMP (section V.3)

Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures Important Identified Risks Special warnings and precaution for use Advice in section 4.2 of SmPC: It is recommended to take a blood count and determine the liver enzyme and kidney values before starting the treatment with Sultiame and subsequently check them weekly during the first month of treatment and then monthly. After six months of treatment between two and four checks annually should be sufficient.

Advice in section 4.4 of SmPC: Patients or their parents should be instructed to consult Blood cytopenia the attending doctor immediately if fever, sore throat, including leucopenia, allergic skin reactions with lymph node swelling and/or None proposed thrombocytopenia flu-like symptoms occur during the treatment with sultiame. Progressive thrombocytopenia or leucopenia accompanied by clinical symptoms such as fever or sore throat requires interruption of treatment. In cases of severe allergic reactions sultiame must be discontinued immediately. Treatment should also be interrupted if a lasting increase in creatinine occurs. The blood count, liver enzymes and urine should be checked regularly (also see section 4.2.)